Crystal form of tipifarnib and method of treatment thereof

Abstract

The present invention relates to novel crystal forms of tipifarnib. Compared with the prior art, the crystal forms of tipifarnib have advantages in crystallinity, hygroscopicity, morphology, form stability and chemical stability. The present invention also relates to the preparation methods of crystal forms of tipifarnib, pharmaceutical composition thereof and their use in preparation for treating and/or preventing abnormal cell growth diseases.

What is claimed is: 
     
       1. A method of treating solid tumors and blood cancers associated with a RAS mutation or over expression in a patient, comprising administering to the patient, a therapeutically effective amount of tipifarnib Form I, having the chemical structure: 
       
         
           
           
               
               
           
         
         wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the tipifarnib Form I, expressed as 2θ angles, has the following characteristic peaks: 8.4°±0.2°, 11.9°±0.2°, 16.4°±0.2°, 17.0°±0.2°, 18.5°±0.2° and 21.7°±0.2°; 
         wherein the solid tumors and blood cancers are selected from the group consisting of lung cancer, pancreatic cancer, colon cancer, thyroid follicular cancer, myelodysplastic syndrome, interstitial cell tumor, melanoma, teratoma, neuroblastoma, glioma, epidermal cancer, salivary gland cancer, skin benign tumor, breast cancer, kidney cancer, bone cancer, ovarian cancer, bladder cancer, liver cancer, multiple neurofibromatosis, hematologic lymphoma, myeloid leukemia, and chronic granulocytic leukemia. 
       
     
     
       2. The method of  claim 1 , wherein the epidermal cancer is head and neck squamous cell carcinoma. 
     
     
       3. The method of  claim 1 , wherein the hematologic lymphoma is peripheral T cell lymphoma. 
     
     
       4. The method of  claim 1 , wherein the tipifarnib Form I is administered as two, three, four or more sub-doses throughout the day. 
     
     
       5. The method of  claim 4 , wherein the sub-dose is formulated as a unit dosage form containing 0.01-500 mg of tipifarnib Form I. 
     
     
       6. The method of  claim 4 , wherein the sub-dose is formulated as a unit dosage form containing 0.01-200 mg of tipifarnib Form I. 
     
     
       7. A method of treating solid tumors and blood cancers associated with a RAS mutation or over expression in a patient comprising administering to the patient, a therapeutically effective amount of tipifarnib Form II, having the chemical structure: 
       
         
           
           
               
               
           
         
         wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the tipifarnib Form II, expressed as 2θ angles, has the following characteristic peaks: 5.3°±0.2°, 6.8°±0.2°, 8.5°±0.2°, 16.3°±0.2°, 18.0°±0.2° and 20.9°±0.2°; 
         wherein the solid tumors and blood cancers are selected from the group consisting of lung cancer, pancreatic cancer, colon cancer, thyroid follicular cancer, myelodysplastic syndrome, interstitial cell tumor, melanoma, teratoma, neuroblastoma, glioma, epidermal cancer, salivary gland cancer, skin benign tumor, breast cancer, kidney cancer, bone cancer, ovarian cancer, bladder cancer, liver cancer, multiple neurofibromatosis, hematologic lymphoma, myeloid leukemia, and chronic granulocytic leukemia. 
       
     
     
       8. The method of  claim 7 , wherein the epidermal cancer is head and neck squamous cell carcinoma. 
     
     
       9. The method of  claim 7 , wherein the hematologic lymphoma is peripheral T cell lymphoma. 
     
     
       10. The method of  claim 7 , wherein the tipifarnib Form II is administered as two, three, four or more sub-doses throughout the day. 
     
     
       11. The method of  claim 10 , wherein the sub-dose is formulated as a unit dosage form containing 0.01-500 mg of tipifarnib Form II. 
     
     
       12. The method of  claim 10 , wherein the sub-dose is formulated as a unit dosage form containing 0.01-200 mg of tipifarnib Form II. 
     
     
       13. A method of treating solid tumors and blood cancers associated with a RAS mutation or over expression in a patient comprising administering to the patient, a therapeutically effective amount of tipifarnib Form III, having the chemical structure: 
       
         
           
           
               
               
           
         
         wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the tipifarnib Form III, expressed as 2θ angles, has the following characteristic peaks: 6.2°±0.2°, 8.8°±0.2°, 15.9°±0.2° and 18.2°±0.2°; 
         wherein the solid tumors and blood cancers are selected from the group consisting of lung cancer, pancreatic cancer, colon cancer, thyroid follicular cancer, myelodysplastic syndrome, interstitial cell tumor, melanoma, teratoma, neuroblastoma, glioma, epidermal cancer, salivary gland cancer, skin benign tumor, breast cancer, kidney cancer, bone cancer, ovarian cancer, bladder cancer, liver cancer, multiple neurofibromatosis, hematologic lymphoma, myeloid leukemia, and chronic granulocytic leukemia. 
       
     
     
       14. The method of  claim 13 , wherein the epidermal cancer is head and neck squamous cell carcinoma. 
     
     
       15. The method of  claim 13 , wherein the hematologic lymphoma is peripheral T cell lymphoma. 
     
     
       16. The method of  claim 13 , wherein the tipifarnib Form III is administered as two, three, four or more sub-doses throughout the day. 
     
     
       17. The method of  claim 16 , wherein the sub-dose is formulated as a unit dosage form containing 0.01-500 mg of tipifarnib Form III. 
     
     
       18. The method of  claim 16 , wherein the sub-dose is formulated as a unit dosage form containing 0.01-200 mg of tipifarnib Form III. 
     
     
       19. A method of treating solid tumors and blood cancers associated with a RAS mutation or over expression in a patient comprising administering to the patient, a therapeutically effective amount of tipifarnib Form IV, having the chemical structure: 
       
         
           
           
               
               
           
         
         wherein, measured using Cu-Kα radiation, the X-ray powder diffraction pattern of the tipifarnib Form IV, expressed as 2θ angles, has the following characteristic peaks: 7.5°±0.2°, 13.9°±0.2°, 15.8°±0.2°, 16.5°±0.2°, 17.4°±0.2° and 18.1°±0.2°; 
         wherein the solid tumors and blood cancers are selected from the group consisting of lung cancer, pancreatic cancer, colon cancer, thyroid follicular cancer, myelodysplastic syndrome, interstitial cell tumor, melanoma, teratoma, neuroblastoma, glioma, epidermal cancer, salivary gland cancer, skin benign tumor, breast cancer, kidney cancer, bone cancer, ovarian cancer, bladder cancer, liver cancer, multiple neurofibromatosis, hematologic lymphoma, myeloid leukemia, and chronic granulocytic leukemia. 
       
     
     
       20. The method of  claim 19 , wherein the epidermal cancer is head and neck squamous cell carcinoma. 
     
     
       21. The method of  claim 19 , wherein the hematologic lymphoma is peripheral T cell lymphoma. 
     
     
       22. The method of  claim 19 , wherein the tipifarnib Form IV is administered as two, three, four or more sub-doses throughout the day. 
     
     
       23. The method of  claim 22 , wherein the sub-dose is formulated as a unit dosage form containing 0.01-500 mg of tipifarnib Form IV. 
     
     
       24. The method of  claim 22 , wherein the sub-dose is formulated as a unit dosage form containing 0.01-200 mg of tipifarnib Form IV.